Radioactive intraluminal endovascular prothesis and method for the treatment of aneurysms

ABSTRACT

A method for increasing the rate of thrombus formation and/or proliferative cell growth of a selected region ( 21 ) of cellular tissue ( 22 ) including the step of endovascularly irradiating the selected region ( 21 ) with radiation, having a dose range of endovascular radiation of about 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about 320 cGy/hr, to increase thrombus formation and/or cell proliferation of the affected selected region ( 21 ). Preferably, the delivery means includes a deformable endovascular prosthesis ( 25 ) adapted for secured positioning adjacent to the selected region ( 21 ) of cellular tissue ( 22 ), and a radioactive source. This source cooperates with the deformable endovascular device ( 25 ) in a manner endovascularly irradiating the selected region with radiation, having the above-indicated dose range and low dose rate of endovascular radiation to increase thrombus formation and/or cell proliferation of the affected selected region ( 21 ).

This is a Continuation application of prior Application No. 09/084,675filed on May 26, 1998, now U.S. Pat. No. 6,296,603 the disclosure ofwhich is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates, generally, to the treatment of vasculardisorders and, more particularly, to the treatment of aneurysms withradioactive intraluminal endovascular prosthesis.

BACKGROUND ART

While conventional bypass graft treatment of aneurysms has steadilyimproved, mortality rates continue to be relatively high in cases suchas abdominal aortic aneurysms. These often asymptomatic aneurysms 15 ofblood vessel 16, as shown in FIG. 1, generally progressively enlarge inmost patients over time, increasing the risk of rupture. Traditionalbypass grafts are then required which are extremely invasive and includeall the risks of open surgeries such as paraplegia, renal insufficiency,and myocardial infarction. Moreover, even three (3) to five (5) yearsafter these surgeries, complications may arise which include concomitantcoronary atherosclerotic disease, graft infection, aortoenteric fistula,thromboembolish, and anastomotic aneurysms.

In the recent past, more innovative approaches have evolved for thetreatment of aneurysms. For example, DACRON® grafts, endovascular stentgrafts and covered stents (referred heretofore generally as “stentgrafts”), which have rapidly developed in an effort to expand stenttechnology, may be employed as a means of aneurysm treatment. Thesehybrid devices combine graft material with a stent or stent-like deviceto provide an expandable, stent-like structure having an imperviousluminal surface.

These combination of features, once implanted, are very conducive toachieve endovascular exclusion of aneurysms. Typically, a graft materialis mounted to and positioned along an exterior circumferential surfaceand/or the interior circumferential surface of the prosthesis in amanner forming an endovascular, blood impervious lumen therethrough. Aproximal end of the graft is preferably endovascularly positioned justupstream from the vascular disorder while a distal end thereofterminates at a position just downstream thereof. As the proximal endand the distal end of the stent graft become anastomosed with the vesselwall, the vascular disorder becomes endovascularly excluded from theblood flow while the is stent graft impervious lumen maintains vesselpatency

Upon proper endovascular deployment and seal formation of the stent,cell matrix formation and tissue healing may commence in the aneurysmalsac and on the luminal surface. For example, in the aneurysmal sacbetween stent graft and the vascular wall, the residual blood clottingand inflammatory response cause cellular proliferation and connectiveformation, forming a matrix that may seal the sac. In addition to thesealing, the resulted wall, which is a combination of prosthesis,connective tissue matrix, and arterial wall provides a conduit supportof proper hemodynamic blood flow.

Intraluminally, thromboembolic processes will occur on the luminalsurface of the graft/stent. Briefly, during this thrombotic phase,platelets and blood clots adhere to the surface to form a fibrin richthrombus. Endothelial cells then appear, followed by intense cellularinfiltration. Finally, during the proliferative phase, actin-positivecells colonize the residual thrombus, resorbing the thrombus.

The primary problem associated with this technique is the time periodrequired for endovascular sealing and repair of the aneurysmal sac.Tissue response to injuries of this nature are generally on the order ofa few months to years. This is especially true for the luminal surfaceof the graft material where organized thrombus formation may bedifficult to achieve. Such endothelial cell growth to line the lumen ofthe stent graft may require years of healing or may never be fullycompleted.

Accordingly, several clinical complications may result due to improperdelayed cellular healing. One of the most prevalent problems,aortoentenic fistula, arises when the seal integrity between the vesselwall and the proximal end of the stent graft is compromised due to slowthrombus formation and incomplete tissue growth. Such upstream, proximalseal breaches cause blood infiltration through the incompleteanastomosis that may lead to abdominal blood loss. Stent graftsefficiency and effectiveness are substantially reduced since the luminalsurface is not re-endothelialized, exposing the foreign surface to therisk of thrombosis and its complications.

There is a need, therefore, to increase the effectiveness and efficiencyof the stent graft to reduce the time period for vascular repair.

DISCLOSURE OF INVENTION

Accordingly, a method is provided for promoting and increasing the rateof at least one of thrombus formation and proliferative cell growth of aselected region of cellular tissue. The method includes the step ofendovascularly irradiating of the selected region endovascularradiation, having a dose range of about 1 Gy to about 600 Gy at a lowdose rate of about 1 cGy/hr to about 320 cGy/hr, to promote thrombusproliferation followed by cellular proliferation of the affectedselected region. Preferably, the dose of endovascular radiation is about1 Gy to about 25 Gy at the graft surface, and at a low dose rate ofabout 1 cGy/hr to about 15 cGy/h. The selected region is preferably theluminal blood contents such as platelets, clotting proteins, and fibrin,while the target cells may include circulatory stem cells and cells fromthe adjacent connective tissue.

In one embodiment, the present method includes the step of positioning adeformable endovascular device, adapted to endovascularly emit theradioactive field, proximate the aneurysm. This step is performed byimplanting the deformable endovascular device adjacent the aneurysm ofthe blood vessel. To generate the radioactive field and before thepositioning step, the present invention includes the step of embeddingradioactive material in the deformable endovascular device.

In another embodiment the embedding step further includes the step of:embedding a central portion of the endovascular prosthesis, sized toextend substantially adjacent the aneurysm when properly positioned,with a first radioactive activity generating the first named radiationacting upon the aneurysm; and embedding the end portions of theendovascular prosthesis, positioned on opposed sides of the centralportion and extending beyond the upstream end and the downstream end ofthe aneurysm, with a second radioactive activity generating a secondradiation having a dosage adapted to decrease thrombus formation and/orcell proliferation of the affected regions flanking the aneurysm.

In still another embodiment, the method of the present inventionincludes the step of positioning an intra-luminal endovascularprosthesis in the vessel proximate the aneurysm; and deploying theendovascular prosthesis from a contracted condition to an expandedcondition, wherein the endovascular prosthesis engages the interiorwalls of the blood vessel forming a void between the endovascularprosthesis and the aneurysm for receipt of the radioactive seeds thereinand such that the radioactive seeds are substantially retained is thevoid by the endovascular prosthesis. In another method, radiosensitizersmay be deposited within the void or the aneurysmal sac, or be insertedinto the aneurysmal contents. These radiosensitizers will be maderadioactive or activated through external beam radiation or endovascularirradiation.

In another aspect of the present invention, a proliferation device isprovided for increasing the rate of proliferative cell growth and/orinduce thrombus formation of a selected region of cellular tissue. Theproliferation device includes a deformable endovascular device adaptedfor secured positioning adjacent to the selected region of cellulartissue, and a radioactive source. This source cooperates with thedeformable endovascular device in a manner endovascularly irradiatingthe selected region with endovascular radiation, having a dose range ofabout 1 Gy to about 600 Gy at a low dose rate of about 1 cGy/hr to about320 cGy/hr, to increase thrombus formation and/or cell proliferation ofthe affected selected region.

The radioactive source is provided by radioactive material embedded inthe deformable endovascular device. In one embodiment, the deformableendovascular device is provided by radioactive coils, endovascularlyirradiating the radiation, sized and dimensioned for receipt in apseudoaneurysm. In another embodiment, for saccular or fusiformaneurysms, the deformable endovascular device is provided by atubular-shaped intraluminal endovascular prosthesis radially expandablefrom a contracted condition and an expanded condition. In the contractedcondition, percutaneous delivery into the blood vessel is enabled, andan expanded condition, the deformable endovascular device radiallycontacts the interior walls of the blood vessel for implanting thereto.In another method, the described endovascular sources can beradiosensitizers or radioactive sources that are coated with biologicfactors such as growth factors, adhesion molecules, and organic matrix

The thrombus formation and/or cellular proliferation device furtherincludes a tubular-shaped sheath device defining a lumen therethrough,and cooperating with the endovascular prosthesis to substantiallyprevent fluid communication between fluid flow through the lumen of theblood vessel and the aneurysm, while maintaining vessel patency. For theaneurysms, the prosthesis is sized and dimensioned to extend beyond anupstream end of the aneurysm and beyond a downstream end of the aneurysmeach by at least about 1.0 mm when properly positioned in the vessel.

BRIEF DESCRIPTION OF THE DRAWING

The assembly of the present invention has other objects and features ofadvantage which will be more readily apparent from the followingdescription of the best mode of carrying out the invention and theappended claims, when taken in conjunction with the accompanyingdrawing, in which:

FIG. 1 is a fragmentary, side elevation view, in cross-section, of atypical fusiform aneurysm.

FIG. 2 is a fragmentary top perspective view, partially broken away, ofan aneurysm incorporating a radioactive stent graft device constructedin accordance with the present invention.

FIG. 3 is a fragmentary, side elevation view, in cross-section, of thestent graft device of FIG. 2 being percutaneously delivered in acontracted condition.

FIGS. 4A and 4B is a sequence of side elevation views, in cross-section,of the stent graft device of FIG. 3 being moved from the contractedcondition to an expanded condition.

FIG. 5 is an enlarged 2-dimensional representation of a multi-cell,pre-deployed stent applicable for use with the present invention.

FIG. 6 is a 2-dimensional dose graphical representation for a Phosphorus32 stent taken substantially along the plane of the line 6-6 in FIG. 5.

FIG. 7 is an enlarged, fragmentary, side elevation view, incross-section, of the expanded stent graft device of FIG. 4B, andillustrating delivery of the endovascular radiation from the radioactivestent.

FIG. 8 is a fragmentary, side elevation view, in cross-section, of thestent graft device and repaired aneurysm of FIG. 4B in a stableproliferative phase.

FIG. 9 is an enlarged, front elevation view, in cross-section, of the ofthe deployed stent graft device taken substantially along the plane ofthe line 9-9 in FIG. 8.

FIG. 10 is a fragmentary, side elevation view, in cross-section, of analternative embodiment stent graft device of FIG. 4B having an externalgraft.

FIG. 11 is a fragmentary, side elevation view, in cross-section, of analternative embodiment stent graft device of FIG. 4B incorporating thedeposition of radioactive seeds.

FIGS. 12A and 12B is a sequence of side elevation views, incross-section, of a pseudoaneurysm having a radioactive coil device ofthe present invention deployed therein.

BEST MODE OF CARRYING OUT THE INVENTION

While the present invention will be described with reference to a fewspecific embodiments, the description is illustrative of the inventionand is not to be construed as limiting the invention. Variousmodifications to the present invention can be made to the preferredembodiments by those skilled in the art without departing from the truespirit and scope of the invention as defined by the appended claims. Itwill be noted here that for a better understanding, like components aredesignated by like reference numerals throughout the various figures.

Attention is now directed to FIGS. 2-4B, 7 and 8 where a method andapparatus are illustrated for increasing the rate of proliferative cellgrowth and/or induce thrombus formation for a selected region 21 ofcellular tissue 22. Briefly, the method includes the step ofendovascularly irradiation the selected region with radiation, having adose range of endovascular radiation of about 1 Gy to about 600 Gy at alow dose rate of about 1 cGy/hr to about 320 cGy/hr, for increasing therate of cell proliferation and/or induce thrombus formation of theaffected selected region. An endovascular device, generally designated23, is adapted for endovascular positioning in close proximity to theselected region 21 of cellular tissue 22. The endovascular deviceincludes a radioactive material or source collectively delivering aradioactive field upon the selected region 21 of a dosage adapted toincrease the rate of cell proliferation and/or induce thrombus formationin the affected selected region 21.

While external exposure of living cells or cellular tissue, in a singleor fractionated dose, to a low level radioactive field has been shown toaccelerate proliferative cell growth, Circulation Research, January1962; X:51-67; Radiotherapy & Oncology 1994; 32:29-36; Int. J. RadiationOncology Biology Physics, 1987; 13:715-722; JACC April1992:19:5:1106-13, endovascular radiation exposure is advantageous inmany respects. For example, this approach tends to be less invasive thanopen surgery. A longer duration of radiation exposure, moreover, may beachieved at lower radiation levels to provide similar radiation doses,as opposed to the single or fractionated doses of the external methodgenerally at higher relative radiation levels. A continuous irradiationenables a continuous promotion of thrombosis on the vascular surface toestablish a matrix for cellular adhesion, while a constant low doseirradiation provides a continuous stimulation of cellular proliferation.As will be discussed in greater detail below, selectively increasingcell proliferation and/or inducing thrombus formation has enormousmedical device and biotechnological implications. Further, this approachis applicable to a wide range of cellular tissue, such as endothelialcells, myofibroblast cells, fibroblast cells, other fibroblast-typecells, inflammatory cells, smooth muscle cells of different phenotypes,spindle-type cells and other connective tissue.

In accordance with the present invention and as will be shown inExperiment A described below, by providing a dose of radioactivity inthe range of about 1 Gy to about 600 Gy at about 0.1 mm from the stentsurface, and at a low dose rate of about 1 cGy/hr to about 320 cGy/hr,the rate of proliferative cell growth and/or thrombus formation may beselectively increased. For example, the rate of proliferative cellgrowth secondary to thrombosis (fibrin deposition, platelets adhesion,and erythrocytes and inflammatory cell aggregation) has been observed toincrease by between about 100% and about 500% in a time frame of about 3months as compared to a control non-radioactive implant. Morepreferably, the radioactive dose is in the range of about 1 Gy to about25 Gy at about 0.1 mm from the stent surface, and at a low dose rate ofabout 1 cGy/hr to about 15 cGy/hr.

To generate a uniform radioactive field, a radioactive material orsource is preferably positioned in close proximity to the selected ortarget region of cellular tissue such that the proper dose ofradioactivity can be applied thereto. This radioactive source ispreferably provided by implantable structures which can be alloyed,embedded, or implanted with the proper radioactivity of radioisotopes sothat the proper dose of endovascular radiation may be endovascularlyemitted to the designated selected region. Such implantable structures,for example, include intraluminal endovascular prosthesis such asstents, stent grafts, or covered stents can be made radioactive toprovide low dose radiation on the luminal surface in promoting fibrindeposition, cellular adhesion, and cellular proliferation on theselected region 21. Other implantable structures include emboli coils 25(as shown in FIGS. 12A and 12B, and to be discussed in greater detailbelow) or the like, which may be irradiated or made radioactive todirect the radiation to target region 44. Still other implantablestructures include radioactive seeds 43 and radiosensitizers (as shownin FIG. 11, and also to be discussed in greater detail below) which maybe deployed to target selected region 21 of the cellular tissue.

Accordingly, the emission of the proper dose of endovascular radiation,as will be apparent below, requires consideration of factors such as thecoil or structure density of the implant device, the proximity to thedesired selected region, the dose rate, volume of the target tissue,specific type of isotopes, and the half-life of the particular type ofradioisotope employed.

Typically, the emission of the radioactive dose from the implantablestructures will be omnidirectional in nature, and generally only affectthe cellular tissues in close proximity to structure. Moreover, theradioisotopes employed for the purpose of the present invention arepreferably alpha, beta or low energy gamma emitters. Otherconsiderations include the predetermined depth of penetration of theradiation to the target region, the vascular and device geometry, aswell as the specific type of isotope, and the half-life of theradioisotope.

Regarding the specific type of isotope, briefly, different types ofisotopes generate different types of radiation. Phosphorus 32 (³²P), forinstance, is a pure beta-particle emitter while Paladium 103 (¹⁰³Pd) isan X-ray photon emitter. Each type of radiation, moreover, generatesdifferent amount of energy which in turn affect the depth ofpenetration, as well as the amount of radiation absorbed by the targetedtissue. Gamma or X-ray photon as a wave, as an example, typicallypenetrate further into the tissue, as compared to alpha particles with amass which penetrate into the tissue the least. Beta particles, on theother hand, typically penetrate into the tissue between the gammaparticles and the alpha particle. Preferably, the device will be usedwith a beta or low energy gamma emitter.

Concomitantly, the described properties of the isotopes must be employedto determined the desired amount of radiation which is to be irradiatedfrom the device. For instance, in order to achieve an equivalent dose ofabout 1470 cGy at about 0.1 mm from the stent surface of a 15 mm lengthstent, a ³²P irradiating stent requires a radioactivity of about 0.93μCi whereas a ¹⁰³Pd irradiating stent requires a radioactivity of about160 μCi.

As set forth above, another consideration is the desired half-life ofthe radioisotope particle which preferably ranges from about one (1)hour to less than about one (1) year. The half-life of the preferredoptimum emitter may be about one (1) day to less than about twelve (12)weeks, and most preferably about two (2) weeks to less than about nine(9) weeks. Depending upon the size of the vascular disorder, the depthof the vessel wall, the dose rate, the required energy level andpredetermined half-life may be selected to optimize vascular repair.Radioisotopes such as Phosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45(⁴⁵Ca), Palladium 103 (¹⁰³Pd) and Iodine 125 (¹²⁵I), for example, havebeen found to be particularly beneficial. For instance, Phosphorus 32 isa pure β-particle emitter, and it typically has a maximum energy of 1.69MeV, an average energy of 0.695 MeV, a half-life of 14.3 days and amaximum particle penetration of a about three (3) millimeters intocellular tissue.

One preferred application for the present invention is for use in thefield of endovascular aneurysm repair, and more specifically, for use incombination with stent graft or covered stent devices or the like. Asshown in FIG. 2, a blood vessel 22 is illustrated having a fusiformaneurysm 21 which is endovascularly excluded from the vessel lumen 26 bya radioactive intraluminal endovascular prosthesis 23 (e.g., a stentgraft). This stent graft 23 is constructed to deliver a dose ofendovascular radiation upon the selected region 21 (i.e., the arterialwall of the aneurysmal sac 27 that is formed between the stent graft andthe wall of the blood vessel), while maintaining vessel patency. Whenthe stent graft is properly positioned and placed in the vessel 22, theaneurysmal sac 27 will be endovascularly excluded from fluidcommunication with the blood flow through the vessel lumen 26.

In accordance with the present invention, exposure of the excludedorganic fluids (primarily blood) contained in the aneurysmal sac 27 tothe above-indicated dose of endovascular radiation increases the rate ofcellular migration and proliferation from the surrounding connectivetissue and vascular wall. Ultimately, cell colonization will be inducedto seal the aneurysmal sac 27 with fibroblasts or spindle-typed cellgrowth to repair the aneurysm (FIGS. 2, 8 and 10). In thisconfiguration, thus, the selected region targeted for irradiationpreferably includes the arterial wall and adventitial tissues such assmooth muscle cells and fibroblats and the blood contents contained inthe excluded aneurysmal sac such as platelets, clotting proteins, andfibrin.

In the luminal aspect, as viewed in FIG. 9 and excluded in FIGS. 2, 8and 10 for clarity, a similar mechanism is taking place in theimpervious graft lumen 32. Thrombus formation in the graft lumen 32, aspreviously indicated, is difficult to achieve in a short time periodsince there is a lack of promotional factors such as natural thrombosis.Exposure of the interior surface of the graft lumen 32 to this low levelradiation substantially induces thrombus formation (i.e., plateletadhesion and fibrin deposition) therealong which, in turn, commencescascade of endothelialization of the lumen. Briefly, during theThrombotic Phase, the initial response is explosive activation,adhesion, aggregation and platelet deposition. In less than twenty-fourhours, fibrin-rich thrombus accumulates around the platelet site. Next,during the Recruitment Phase, the initial appearance of cellularinfiltration (monocytes and macrophages) occurs, followed by endothelialcells 24. Finally, during the Proliferative Phase, the actin-positivecells colonize the residual thrombus, resorbing the thrombus. SmoothMuscle Cell migration and proliferation into the degenerated thrombuscreates substantially increased neointimal volume.

Exposure of the blood contents in the gap 27 to this dose of radiationhas been determined to be beneficial in two respects. First, the rate ofthrombotic formation in the luminal surface of the graft has been foundto substantially increase which ultimately shortens the ThromboticPhase. For example, a dose of endovascular radiation of between about 1Gy and about 50 Gy has been shown to induce thrombus formation along theinterior surface in 28 days or by a rate increased by 4-20 times (SeeExperiment A). By inducing thrombosis, which is the initial step towardsendothelization of the lumen interior surface 29, proliferative cellularhealing can commence. One hypothesis for the inducement of thrombusformation is due to the inflammatory response which induces theplatelets, erythrocytes, and fibrin to adhere to the luminal surface 29at a faster rate.

Second, the increased proliferative cell growth shortens both theRecruitment Phase and the Proliferative Phase in both theendothelialization of the lumen interior surface, as well as the repairof the aneurysmal sac 27. One theory for the increase in the rate ofcell proliferation and is that the low level radiation causes a mildstimulation to the cells such as smooth muscle cells, inflammatorycells, and fibroblasts. In response, increased biochemical moleculessuch as cytokines to the region occurs which increases the rate ofvascular repair and further enhances the cascade of healing.

Referring back to FIGS. 3 and 4B, one technique of deployment of thestent graft 23 of the present invention is illustrated. The delivery maybe performed through conventional open surgery or endovascular cut-downtechniques. More preferably, the stent-graft delivery is performedpercutaneously using a guide wire (not shown) positioned through vessel22 and conventional stent-graft delivery system 28. A balloon expandableradioisotope stent graft 23 is provided having a deformable, tubularstent 25 and a thin walled material graft 30 coaxially aligned andmounted onto balloon 31 at a distal portion of stent-graft deliverysystem 28. FIGS. 3 and 4A illustrate the balloon and mounted stent graft23 in a contracted condition which enables percutaneous advancement ofthe distal portion of the catheter through the vessel to the treatmentsite. Once endovascularly positioned, selective inflation of the balloon31 radially expands the stent graft 23 from the contracted condition(FIG. 4A) to the expanded condition (FIG. 4B). Such exposure secures thestent against and into the intima of the vessel to prevent migration ofthe stent, and to promote anastomoses with the stent. Use of theradiation shields or the like may be employed to reduce unnecessaryexposure to the radioactive field during percutaneous delivery. One suchpatented radiation shield for radioisotope stents is disclosed in U.S.Pat. No. 5,605,530 to Fischell et al.

It will be appreciated that the stent graft 23 is sized and dimensionedsuch that an upstream portion of the stent graft 23 is adapted forpositioning just upstream of the aneurysm 21, while a downstream portionthereof is adapted positioning just downstream of the vascular disorder(e.g., aneurysm 21) each by at least about 1.0 mm. Preferably, theseanchor regions of the stent, which may be provided by hooks, sutures orshape memory alloys such as NiTi, typically contact the intimal surfaceof the vessel along a sufficient longitudinal dimension to anchor thestent in place. When combined with the tubular sheath device or materialgraft 30, a blood impervious luminal surface 29 of the material graftendovascularly excludes the aneurysm 21 from the blood flow lumen todefine the aneurysmal sac 27. Moreover, the material graft 30 and theexpanded stent 25 cooperate to provide graft lumen 32 therethrough tomaintain vessel patency.

Another stent delivery approach for vascular disorders is deliverythrough conventional cut-down techniques. Briefly, in this more invasivesurgical technique, an incision may be made at the aneurysmal site fordirect insertion of the stent graft therein. Upon proper deployment andanchoring of the stent graft, the incised arterial wall is opposed andis sutured together to close the incision, enveloping the graft withinthe lumen.

As set forth above, one problem associated with these prior art stentgraft assemblies was the seal formation and seal integrity at theupstream portion of the stent graft with the interior wall of the bloodvessel 22 (i.e., the intima). This seal is important to secure isolationof the aneurysmal sac 27 from the blood vessel lumen 26 which isdesirable to be reproducible and to be performed as quickly as possible.In accordance with the present invention, in the aneurysmal sac aspect,the radioactivity endovascularly emitted from the stent surface directlyupon the target endothelial cells of the intima at the proximal anddistal end portions end 40, 41 of stent graft substantially increasesanastomosed proliferative cell matrix growth thereof at these contactregions. Hence, seal formation between the vessel 22 and the contactingproximal and distal end portions of the stent graft is substantiallyfacilitated by the increase rate of proliferative cell growth. While notillustrated at the end portions of the stent graft in FIGS. 2, 8 and 10for clarity, upon proper accelerated healing in the advancedproliferative stage, the neointimal layer 34 (i.e., the matrix formationwith its cellular constituents) and the new endothelial layer 24 (FIG.9) lining the stent graft lumen 32 grow over the proximal edge 33 andthe distal edge 35 of the material graft 30, and the correspondingproximal and distal edge 36, 37 of the stent 25 to seal the aneurysmalsac 27 from the vessel lumen 26 and the graft lumen 32

Further, once the aneurysmal sac 27 is endovascularly excluded,thrombosis naturally commences therein which may be further advanced bythe emitted radiation. However, as the radioactivity is endovascularlyemitted from the stent surface in the proper dose and at the proper doserate to the target fluids contained in the excluded aneurysmal sac 27(FIG. 7), the residual blood clotting and inflammatory response induceproliferative cell growth and connective formation. In the advancedstages of healing, as best viewed in FIGS. 8 and 9, an arterial media 39forms the connective tissue growth which eventually binds the vesselwall 26 against the exterior circumferential surface of the stent graft.

In the luminal aspect, as shown in FIG. 9, the proper dose ofendovascular radiation emitted from the stent 25 will induce thrombusformation on the interior surface 29 of the material graft 30 definingthe lumen. As the platelets and fibrin are induced to adhere to theinterior surface 29 by the emitted radiation, a fibrin rich thrombuslayer with trapped erythrocytes is deposited along the entire length ofthe lumen. This initiation of the localized thrombotic process functionsas the initial building blocks for endothelialization of the stent graftlumen. In the recruitment phase, endothelial cells subsequently appear,followed by intense cellular infiltration. Finally, during theproliferative phase, actin-positive cells colonize the residualthrombus, resorbing the thrombus and forming a thin intima layer ofendothelial cells lining the interior surface. In accordance with thepresent invention, this low dose endovascular radioactive stent grafthas been shown to increase the rate of endothelialization about severaltimes faster than conventional techniques.

To further facilitate platelet adhesion and thrombus formation, and/orcell proliferation, the interior surface 29 of the material graft 30 mayinclude a biomaterial coating of biological growth factor to form atemplate in which cells may adhere. One such organic substance ispreferably provided FIBRONECTIN® or collagen or the like. Additionally,the use of the present invention device in combination with proteins(e.g., fibroblast growth factors), or gene thereapy (e.g., VEGF) canprovide beneficial results.

It will be appreciated that the endovascular prosthesis 23 may beprovided by any conventional stent design capable of expansion andretention from a contracted condition to an expanded condition. Forinstance, a tubular slotted stainless steel Palmaz-Schatz stent fromJohnson and Johnson Interventional Systems may be employed with thepresent invention. Another stent pattern, as shown in FIG. 5 which isthe subject of a stent design disclosed in U.S. Pat. No. 5,697,971 toFischell et al. and incorporated by reference herein in its entirety,may also be deployed with the present invention. As mentioned, one ofthe factors determining the amount of irradiation of the stent,necessary to endovascularly irradiate the appropriate dose ofendovascular radiation to the selected region, is the stent design. Forexample, the denser the stent pattern or number of coils, the moreuniform the dose of endovascular radiation. For the stent design ofstent 25 illustrated in FIG. 5, the stent activity is preferably betweenabout 0.07 μCi/mm to about 0.8 μCi/mm to provide a dose of endovascularradiation in the range of about 1 Gy to about 600 Gy from about 0.1 mmof the stent surface where the selected region 21 is preferably about1.0 mm to about 3.0 mm from the surface of the stent. More preferably,the stent activity is between about 0.13 μCi/mm to about 0.2 μCi/mm.

This dose distribution is better illustrated in FIG. 6 which representsa two-dimensional graph of the Dose to Tissue vs. Distance From theSurface of the Stent. In this configuration, the radioactive fieldbecomes relatively more uniform as little as 0.5 mm from the stentsurface which endovascularly irradiates a dose of about 10,000 cGy; andsubstantially more uniform from about 1-3 mm away from the stentsurface. This graph represents measurements taken from stent designsubstantially similar to that of the '971 patent irradiated withphosphorus 32 (³²P) isotope with an activity of about 1.33 μCi/mm with a3 month total dose.

In the preferred embodiment, the material graft 30 is provided by arelatively flexible material composition which enables expansion fromthe contracted condition to the expanded condition and is impervious toblood flow. Such materials may include DACRON®, TEFLON®, PET(Polyethylene Terephthalate), polyester or a biocompatible metallic meshmaterial. This material graft 30 is affixed to the stent 25 usingconventional anchor means employed in the field to prevent migrationthereof along the stent. Further, as best viewed in FIGS. 3-4B, theproximal edge 33 and the distal edge 35 of the material graft 30preferably terminate at or at a position slightly less than thecorresponding proximal and distal edge 36, 37 of the stent 25. Thisconfiguration prevents any overhang of the ends of the material graftinto either of the openings of the stent to minimize any current orpotential occlusion of the stent passageway. This is especiallyproblematic should excess in-growth be experienced at the ends of thestent graft were formation of the seal is to occur.

Once the stent graft 23 is properly positioned and moved to the expandedcondition so that the aneurysmal sac is occluded from the lumen 26, theradioactive stent 25 of the present invention will begin endovascularlyirradiating or delivering radioisotopes to the materials contained inthe sac in the proper dose of endovascular radiation (FIG. 7). Asmentioned above and in accordance with the present invention, thethrombotic phase is accelerated by the radioactivity, as is therecruitment phase and the proliferative phase for endothelialization ofthe aneurysmal sac 27 for aneurysm repair (FIG. 8).

In an alternative embodiment, the stent graft may be configured toirradiate different levels of radiation longitudinally and/orcircumferentially along the stent. For example, in a peripheral aneurysmwhere the dilation is not circumscribed, full circumferential healingmay not be necessary along the vessel wall. Hence, the endovascularirradiation from the stent may not need to be uniformly applied, aswell. In another example, a stent graft having an uniform radioactivitylongitudinally therealong will not emit a uniform dose rate of radiationnear the proximal and distal ends there, as compared to the center ofthe stent graft, due to the distribution geometry. Accordingly, it maybe desirable to selectively apply the desired amount of radioactivityalong the geometry to either increase or inhibit cellular proliferation.

Moreover, to limit potentially occlusive in-growth at the proximal anddistal ends of stent graft 23, the proximal and distal end portions ofthe stent which anchor the stent to the vessel may have differentactivities as compared to the growth inducing radioactivity of thecentral portion 38 of the stent (FIG. 8). The proximal and distal endportions 40, 41 of the stent graft 23 which physically contact theendothelial cells of the intima may be embedded or irradiated with anactivity which reduces proliferative cell growth. However, it will beappreciated that the reduction of cell growth should not be at amagnitude where sealing time and reproducibility are detrimentallyaffected, or where seal integrity formation at the end portions iscompromised.

Such secondary stent activities and resulting doses of endovascularradiation are disclosed in U.S. Pat. Nos. 5,176,617 and 5,059,166 toFischell et al., incorporated herein by reference. Preferably, thesecondary activities are positioned on opposed sides of the centralportion 38 and extending beyond the upstream end and the downstream endof the aneurysm.

Another approach to limit occlusive in-growth at the proximal and distalend portions of the stent graft would be to subsequently expose thoseportions to higher levels of radiation which decrease cellproliferation. For example, after the radioactive stent graft of thepresent invention has been deployed and the proximal and distal endportions have been sufficiently anastomosed to seal and endovascularlyexclude the aneurysmal sac from the vessel and graft lumen, the endportions may be irradiated with radioactive isotopes at levelssufficient to decrease or prevent further cell proliferation. It will beappreciated, however, that such radiation dosages should not be so highas to damage the target tissue at the proximal and distal end portions.

Delivery of such radiation may be performed endovascularly throughcatheters or the like, or may be performed through more externaltechniques such as external beam irradiation.

This technique may also be applied to smaller branch vessels which areto be anastomotized to the side of stent graft (not shown). In theseconfiguration, embodiment, after the vessel has sufficient anastomosedto the stent graft, the immediate area surrounding anastomosis site maybe irradiated with the above mentioned higher level of radiation todecrease or prevent further cell proliferation.

In another alternative embodiment, the tubular material graft 30 may bepositioned along the exterior surface of the stent 25, as shown in FIGS.10 and 11. This covered stent also provides an impervious luminalsurface 42 which prevents fluid communication between the stent-graftlumen 32 and the aneurysmal sac 27 so that thrombus formation and cellgrowth may be accelerated with the proper dose of radioactivity.

In yet another alternative embodiment, radioactive seeds 43 maybeimplanted into the excluded aneurysmal sac 27 in combination with eithera stent graft or covered stent. This radioactive seeding may be employedalone with a non-radioactive stent 25, or together with a radioactivestent. As shown in FIG. 11, the cumulative affect of the radioactiveseeds produce the preferred dose of radioactivity to increase thecell/thrombus proliferation. In the preferred form, these particles 43may be provided by stainless steel or platinum seeds about 0.1 mm toabout 2 mm in diameter, and embedded with the proper activity ofradioisotopes. Depending upon the desired density distribution of theimplanted seeds in the aneurysmal sac 27, the activity of the seeds canbe determined to produce the cumulative dose of endovascular radiationto be delivered to the selected region 21. In the preferred form, thedensity of the distribution of radioactive seeds is about 2particles/cm³, while the activity per seed is about 0.1 μCi to about 0.5μCi.

Once the stent graft or covered stent 23 is properly deployed orpartially deployed, the radioactive seeds 43 may be deposited into theoccluded aneurysmal sac 27 to induce thrombus formation and accelerateproliferative cell growth. Preferably, the seeds are implanted throughconventional injection techniques, through lumens of a (seed) deliverycatheter or placement during open surgery.

In still yet another embodiment, the graft may be embedded with aradiosensitizer capable of being activated by either an external orendovascular radiation source. Once activated, the radioactive stentwould subsequently emit the proper dose of radiation to increase therate cell proliferation and/or induce thrombosis. Another approach wouldbe to deliver or seed the aneurysmal sac 27 with a radiosensitizer,similar to the radioactive seeds, and then activate the same to emit theproper dose of radiation. One such radiosensitizer, for example, mayinclude halogenated pyrimidines, while the activator may be provided byan X-ray, ultraviolet, and external electron beam source.

Turning now to FIGS. 12A and 12B, a saccular or pseudoaneurysm 21, suchas an intracranial aneurysm, is illustrated which is formed along anupper portion of vessel 22. In accordance with this embodiment of thepresent invention, a radioactive coil emboli 25 may be implanted andanchored in the aneurysmal sac 44 of the pseudoaneurysm 21 to induceintravascular thrombosis (FIG. 12A). By irradiating or embedding thesetypically stainless steel or platinum coils with radioactivity, thrombusformation can be accelerated when the coils 25 deliver endovascularradiation of the proper radioactive dose to the aneurysmal sac 44 of thepeusdoaneurysm 21. Once the thrombus phase is complete, the rate of therecruitment phase and the proliferative phase are also increased by theradioactivity emanating from the coil. As shown in FIG. 12B, thepseudoaneurysm 21 will then be repaired once the cell growth fill in theaneurysmal sac 44 of the pseudoaneurysm 21.

Similar to the radioactive seeds, the activity of the coils depends uponthe predetermined coil density when positioned in the aneurysmal sac 44of the pseudoaneurysm. Of course, a higher coil density to increasethrombogenicityic will require a smaller activity to generate a uniformradioactive field in the desirable range of about 1 cGy to about 600cGy.

Still other embodiments may include a radioactive external beam device(not shown) which may be positioned on the outside of the vessel anddisposed adjacent to the aneurysm sac or gap. This device may be used incombination with a radioactive or non-radioactive stent graft device topromote the rate of vascular repair of the vessel. In thisconfiguration, the beam may be configured to focus the endovascularradiation toward the aneurysmal sac.

In still other combinations, the radioactive coil emboli may be employedin the aneurysmal sac in combination with a radioactive ornon-radioactive stent graft (not shown). In this manner, the coil emboliwill function in the same manner as the radioactive seeds.

A radioactive catheter wire (not shown) may be advanced percutaneouslythrough the vessel and into the aneurysm to promote and acceleratethrombosis and vascular repair. This temporary radioactive wire may thenbe removed upon completion of the proper dose of endovascular radiation.This configuration may also be applied in combination with radioactiveor non-radioactive stents, stent grafts, covered stents, coil emboli orthe seed embodiments above-mentioned.

As mentioned above and in accordance with the present invention, theradioactive stent, coil emboli or seed embodiments may apply any othercellular growth inducing materials which are utilized to promotecellular growth. For example the exterior stent surface or the exteriormaterial graft surface, as well as the graft interior surface, may becoated with a conventional tissue growth inducing biomaterial such asFIBRONECTIN®, VEGF or the like.

Other medical application upon which the present invention may applyinclude the rate of increase of cell growth proliferation of vasculardissections, wound healing, wound closures, atrial septal defects,atrial venus malformation, orthopedic implants to encourage osteoblastgrowth with the use of bone chip gel with radiation, and varicose veins,to encourage cell proliferation in obliteration of the lumen.

The following Experiment A serve to more fully under the above-describedinvention, as well as to set forth the best mode contemplated forcarrying out various aspects of the invention. It is to be understoodthat this example in no way serves to limit the true scope of theinvention, but rather are presented for illustrative purposes.

EXPERIMENT A

Overview: A radioactive stent in accordance with the present inventionwas placed within the artery and the vascular response to theirradiation was examined at different time points after the stentplacement. The endovascular irradiation (brachytherapy) was observedusing the IsoStent BX™ radioactive stents. The isotopes were Phosphorus32 (³²P) and Yttrium 90 (⁹⁰Y). Briefly, ³²P is a pure beta-emittingparticles with a half-life of 14.3 days, an average energy of 0.60 MeV,and a maximum energy of 1.7 MeV. The ⁹⁰Y is also a pure beta-emittingparticles with a half-life of 2.7 days, an average energy of 0.90 MeV,and a maximum energy of 2.3 MeV. These radioactive stents were implantedin the coronary arteries of forty Yucatan miniature pigs, and thevascular response was analyzed for three (3) months after theimplantation.

Stent Preparation: Proprietary stent of 15 mm length, tubular stainlesssteel IsoStent BX™ stents were made radioactive by either the direct ionimplantation method or the radiochemical method. In the study with ³²P,this radioisotope was directly ion implanted beneath the surface of themetal (Forschungszentrum Karlsruhe, Karlsruhe, Germany) to yield anactivity level of 0.1, 1.0, 1.5, 3.0, 6.0, and 12.0 μCi at stentimplantation into the animals. Such activity levels yielded a total 3month dose of ³²P in the range from 1.0 Gy to 600 Gy at 0.10 mm from thesurface of the stents. The corresponding initial maximum dose-rate at0.10 mm from the stent surface ranged from 1 cGy/hr to 120 cGy/hr. Inthe study with ⁹⁰Y, the radioisotope was radiochemically coated onto thestent surface to yield an activity level of 1.0, 2.0, 4.0, 8.0, 16.0,and 32.0 μCi. The total 3 month dose ranged from 3 Gy to 280 Gy at 0.10mm from the stents surface, and the corresponding initial maximumdose-rate ranged from 5 cGy/hr to 320 cGy/hr. The control sample stentsin this study were the non-radioactive BX™-stents of 15 mm in length andwere fabricated in a manner similar to the radioactive stents except forion implantation of ³²P or radiochemical process. All these stents werepre-mounted on PAS balloon catheters (Fischell IsoStent™ with deliverysystem, Johnson & Johnson Delivery System).

The stent radioactivity was determined as follows: In the ³²P stents,the activity level of each stent was determined by comparison tostandard ³²P sources of known activity using liquid scintillationcounting methods. After ion implantation, the stents were placed in asealed cylindrical acrylic resin radiation shield and gamma-raysterilized in a conventional manner. The stents were then implanted whenthe radiation level had decreased to the desired activity. The radiationlevels at implantation were determined by calculations that used theknown half-life for ³²P (14.3 days) and the following standard“activity” equation: A_(t)=A₀e^(−kt), where A_(t) is the activity levelat the time (μCi), A₀ is the initial activity level (μCi), t is time indays, and k is the rate constant.

Animal Model: In the ³²P study, 40 Yucatan miniature swine underwentplacement of 70 stents (50 radioactive ³²P (β-particle) BX stents, and20 control, non-radioactive BX stents) in the left anterior descending,left circumflex or right coronary artery. In the ⁹⁰Y study, there were72 radioactive BX ⁹⁰Y stents and 28 control, non-radioactive stents thatwere implanted in the coronary arteries of 40 Yucatan miniature swine.Animals were medicated with aspirin 650 mg, nifedipine extended release30 mg and ticlopidine 250 mg by mouth the evening prior to stentplacement. Under general anesthesia, an 8F sheath was placed retrogradein the right carotid artery, and heparin (150 U/kg) was administeredintra-arterial to achieve an activated clotting time greater than 300seconds (Hemochron, International Technidyne, Edison, N.J.). Aftercompletion of baseline angiography, the 15 mm stents were implantedusing the guiding catheter as a reference in order to obtain a 1:1.2-1.3stent to artery ratio (i.e., 20%-30% oversizing) as compared with thebaseline vessel diameter. Stents were manually crimped ontonon-compliant 3.0 or 3.5 mm diameter 10 mm length angioplasty balloons(SCIMED, Maple Grove, Minn.). Placement of the stent was completed withtwo balloon inflation at 12 or 14 ATM for 30 seconds. Angiography wascompleted after stent implant to confirm patency of the stent andside-branches as well as to assess for migration or intra-luminalfilling defects. The animals were allowed to recover and returned tocare facilities where they received a normal diet and aspirin 81 mgdaily. The animals were returned for coronary angiography and euthanasia3 months after the stent implantation. Immediately following theangiography, the animals were euthanized with a lethal dose ofbarbiturate. The hearts were harvested and the coronary arteries wereperfusion-fixed with 10% neutral buffered formalin at 60-80 mmHg for 30minutes via the aortic stump.

Histology: Non-contrast postmortem radiography was completed on eachstented vessel prior to sectioning in order to assess stent expansionand structural integrity. The fixed hearts were X-rayed and the stentedcoronary artery segments were carefully dissected from the epicardialsurface of the heart. Control sections of the adjoining non-stentedartery were taken from the proximal and the distal ends. The stentedarteries were then processed in graded series of alcohol and xylene andembedded in methyl methacrylate. The plastic embedded stents are thencut with a rotatory diamond edged blade into 6.0-8.0 mm blocks from theproximal, mid, and distal segments of the stent and then sectioned witha stainless steel carbide knife into 4-5 μm sections. Arterial sectionsproximal and distal to the stent were processed in paraffin andsectioned as above. All histologic section were stained withhematoxylin-eosin and Movat pentachrome stains. All three sections wereexamined by light microscopy and used for morphometric measurements. Theparaffin embedded sections were similarly cut and stained in a routinemanner and examined for any abnormalities.

Statistical Analysis: The mean injury score, neointimal area and percentarea stenosis were determined. Data are expressed as the mean±theStandard Deviation (SD). Lesion morphology and injury score werecompared for the control and radioactive stents using ANOVA with a posthoc analysis for multiple comparisons. The stent activity, neointimal,and medial cell density were analyzed with a polynomial regression modelto derive a slope, intercept and correlation coefficient to determinerelations. Significance was established with a p value SD. Lesionmorphology and injury score were compared for the control andradioactive stents using ANOVA with a post hoc analysis for multiplecomparisons. The stent activity, neointimal, and medial cell densitywere analyzed with a polynomial regression model to derive a slope,intercept and correlation coefficient to determine relations.Significance was established with a p value<0.05. All statistics werecalculated using Starview 4.5 (Abacus, Berkeley, Calif.).

Results

Procedural and postoperative: One animal died due to balloon ruptureduring implantation of a control stent resulting in severe coronaryspasm and refractory ventricular arrhythmias. Ventricular tachycardiaand fibrillation occurred in one additional animal which required DCcardioversion to restore a normal sinus rhythm. All animals had a normalpostoperative recovery and resumed a normal pig chow diet (Purina) thefollowing morning after stent implant. There were no cases of woundinfection, incomplete healing or dehiscence. Daily observation of theanimals indicated normal behavior and dietary intake. All animals had astable or mild increase in body weight during the study (baseline29.2+5.1 kg versus 31.2+5.5 kg at following-up, p<0.001).

Blood samples were obtained for complete blood counts in all animalsprior to and at 28 days after stent placement. The mean white blood cellcount was similar at stent implant and on follow-up study (baseline12.5+3.0×10³ cells/mm³ versus follow-up 12.6+4.8×10³ cells/mm³, p=0.97).The mean hemoglobin concentration was normal baseline (10.5+1.5 g/dl)and was not significantly different 28 days after stent placement(10.3+1.2 g/dl, p=0.72). The baseline (mean 429+137×10³ cells/mm³) andfollow-up mean (mean 493+110×10³ cells/mm³) platelet count were in anormal range for all animals.

Follow-up Angiography: Angiography was completed at 3 months after stentplacement. Two animals did not have angiographic study because of theprocedural or post operative complications previously described. In the33 animals with 28 day angiographic follow-up, sixty-six of 66 stents(100%) were patent with normal angiographic coronary flow. There were nocases of stent migration or side-branch occlusion. Quantitative analysisof the coronary angiograms was note completed for this study.

Necropsy: The gross appearance of the mediastinum, pericardium andmyocardium was normal in all animals. The pericardial fluid was clearand straw colored in all cases. There were no cases with bloody orpurulent pericardial fluid. The epicardial surface of the heart andstented arterial segments when visible were normal in all cases.

Histology: The radioactive groups for P³² and Y⁹⁰ showed a luminalsurface with a complete re-endothelialization. The neointima of theradioactive groups had a substantially higher neointimal area andthickness compared to the non-radioactive stents, consisting of smoothmuscle proliferation and matrix formation. A few inflammatory cells werefound on the luminal surface as well as the neointima. The adventitialshowed occasional fibrosis.

In comparing the ³²P to ⁹⁰Y groups, the ⁹⁰Y groups revealed a morecomplete re-endothelialization and healing. This may due to the shorterhalf-life of ⁹⁰Y, which is 2.7 days as compared to 14.3 days.

The following vascular response parameters were determined: percentluminal reduction, percent adventitial change, presence of thrombus,percent internal elastic lamina disruption, percent external elasticlamina disruption, percent medial disruption, and percent ofinflammation.

The following morphometric measurements were taken: external elasticlamina area, internal elastic lamina area, stented lumen area, medialarea, thrombus area, intimal thickness and area, percent stenosis, andinjury score.

TABLE 1 Morphometric measurements of ³²P radioactive stent study neo-neo-intimal μCi/15 m EEL area, IEL area, Lumen Medial intimal thickness,m stent mm² mm² area, mm² area, mm² area, mm² mm2 % stenosis 0 8.34 ±1.63 6.54 ± 1.12 3.48 ± 1.06 1.81 ± 1.06 3.06 ± 1.58 0.41 ± 0.26 45.1 ±18.1 0.1 7.32 ± 0.98 5.73 ± 0.84 3.90 ± 0.84 1.59 ± 0.28 1.82 ± 1.100.22 ± 0.18 30.7 ± 16.2 0.5 7.21 ± 0.97 5.97 ± 0.89 4.06 ± 1.04 1.25 ±0.55 1.91 ± 1.07 0.22 ± 0.15 31.5 ± 15.5 1 7.17 ± 1.39 6.08 ± 1.05 1.89± 0.42 1.09 ± 0.39 4.19 ± 0.80 0.68 ± 0.81 68.7 ± 4.9  1.5 5.90 ± 1.024.85 ± 0.73 1.92 ± 0.91 1.05 ± 0.32 3.93 ± 0.72 0.48 ± 0.18 60.9 ± 15.33 7.73 ± 0.75 6.46 ± 0.62 1.82 ± 1.07 1.26 ± 0.18 4.64 ± 1.25 0.66 ±0.13 71.4 ± 17.1 6 7.25 ± 2.16 6.17 ± 1.65 0.57 ± 0.53 1.09 ± 0.51 5.60± 2.12 0.81 ± 0.04 89.3 ± 9.80 12 8.38 ± 1.77 6.37 ± 1.24 2.14 ± 1.462.01 ± 1.01 4.22 ± 1.56 0.64 ± 0.34 66.6 ± 21.2

TABLE 2 Morphometric measurements of ⁹⁰Y radioactive stent study.neo-intimal μCi/15 m EEL area, IEL area, Lumen Medial neo-intimalthickness, m stent mm² mm² area, mm² area, mm² area, mm² mm² % stenosis0 8.55 ± 0.92 6.80 ± 0.77 4.07 ± 1.22 1.75 ± 0.33 2.34 ± 0.98 0.28 ±0.20 40.0 ± 17.2 2 8.32 ± 1.02 6.71 ± 0.88 1.92 ± 0.91 1.61 ± 0.41 2.23± 1.25 0.27 ± 0.22 33.5 ± 18.1 4 8.43 ± 1.44 7.01 ± 1.17 1.82 ± 1.071.43 ± 0.33 2.15 ± 0.66 0.24 ± 0.10 31.1 ± 10.9 8 7.71 ± 1.21 6.24 ±1.13 2.60 ± 1.01 1.47 ± 0.26 3.64 ± 1.26 0.54 ± 0.23 57.7 ± 15.5 16 8.22± 1.26 6.61 ± 1.29 2.50 ± 1.18 1.60 ± 0.83 4.11 ± 1.38 0.61 ± 0.20 61.6± 18.6 32 7.13 ± 1.27 5.97 ± 1.13 2.14 ± 1.46 1.16 ± 0.26 4.07 ± 1.680.57 ± 0.28 67.6 ± 22.7

For both ³²P and ⁹⁰Y studies, the radioactive stents showed are-endothelialized lumen. The neo-intima showed a dose dependenceincrease of cellular proliferation and cell matrix formation. Thesefindings were evidenced by the increase of neointimal area and thicknessas a function of increased irradiation as compared to the controls. Themedial layer beneath the struts was thinned. The adventitial showed adose dependence increased in fibrosis.

Discussion

The effects of radiation on vascular cellular proliferation have beenextensively studied. Lindsay et al applied X-ray radiation on theexposed dog aorta (Circulation Research, volume X, January 1962, page:51-60). The animals were sacrificed at different time points, rangingfrom 2 to 48 weeks following irradiation. The results showed that therewas an accentuation of fibrocellular proliferation at a single dose of 8Gy to 15 Gy and 30 Gy to 55 Gy. The latter group showed less vascularproliferation than the former. The range of the estimated dose-rate wasfrom 176 cGy at the dorsal wall to 320 cGy at the surface of the ventralwall. The fibrocellular proliferation increased with time after theirradiation. The histopathologic findings showed intimal thickening withfibroblastic-like proliferation and some matrix formation. There wasfibrosis of medial and adventitia in response to irradiation. Similarfibroblastic proliferation was observed when the aorta of the dogs wereexposed to a single dose of external electron irradiation of 10-95 Gy(Circulation Research, volume X, January 1962, page: 61-67).

Other studies examined the vascular response when the radiation dose wasfractionated. The results showed similar increased in cellularproliferation. In one study, the rat aorta was exposed to X-rayirradiation of 47 Gy with fractionation of 5.2 Gy (Radiotherapy &Oncology 32, 1994, page 29-36). There was an increased in fibrogeniccytokines and inflammatory cells that led to cellular proliferation,resulting in increased fibrosis. In another study with the aorta of thedogs, using 22-86 Gy in fractionation, there was a marked increased inintimal and medial proliferation (Int. J. Radiation Oncology BiologyPhysics, volume 13, page 715-722). The adventitial and perivasculartissue showed increased fibroblastic response. The 22-38 Gy group showed4 fold and the 60-80 Gy showed about 20 fold increased in intimalthickness as compared to the control group.

Similar vascular response to external beam irradiation was also observedin the coronary arteries. Schwartz et al exposed the coronary arteriesof the pigs to a single dose of x-ray radiation of 4 Gy to 8 Gy in oneday (JACC Volume 19, No. 5, April 1992:1106-13). The results showed a20% to 50% increase of neointimal proliferation as compared to thecontrol group.

The current experiments, applying endovascular radiation to pig coronaryarteries, showed similar results. These studies involved the use ofbeta-emitting radioactive stents for endovascular delivery of radiation.As shown in Table 1 and Table 2, a significant neointimal proliferativeresponse was observed in the ³²P and ⁹⁰Y groups as compared to thenon-radioactive group. More importantly, all the radioactive and thenon-radioactive groups showed no bio-compatibility related problems.There was no evidence of foreign body giant cell reaction or excessiveinflammatory response. The histologic sections showed no evidence ofradiation injury such as necrosis of the arterial wall or the matrix,and the adventitia and the arterial wall revealed no evidence ofsignificant inflammatory reaction.

The presence of trapped erythrocytes and fibrin material within theneointima indicates that radiation induces thrombosis on the luminalsurface. The histopathologic results showed an increase of 100% to 500%of cellular proliferation, which indicates that the radiation promotescellular growth. Although the 0.1 and 0.5 μCi of the ³²P groups showed alesser neointimal thickness and a lower precent restenosis as comparedto the control group, the results suggested a faster and a more completere-endothelialization of the luminal surface. It is believed that thelower amount of irradiation on the surface may stimulate and activatethe proliferation of the endothelial cells.

The results indicate that the dose for inducing localized thrombosis andcellular proliferation is 1 Gy to 600 Gy for ³²P and 3 Gy to 280 Gy for⁹⁰Y. However, it is believed that the total dose that will result incellular proliferation range from 1 Gy to 600 Gy, regardless of theisotopes used. This is the case because the principle of radiobiologyhas shown a given cellular tissue will yield the same or similar resultsif given the same dose of radiation regardless of the isotope (i.ebeta-emitting or gamma-emitting isotopes) or the method of delivery (i.eendovascular or external beam radiation, single dose or fractionation).The corresponding dose rate for inducing cellular proliferation alsofollows the same principle; that is, the initial dose rate of 1 cGy/hrto 320 cGy/hr will promote cellular proliferation regardless of theisotopes used or the methods of irradiation. As for the amount ofactivity on the stent, the total activity to achieve the desiredcellular proliferation (in μCi) will vary, depending on the isotope usedand volume of target tissue. For example, to achieve a total dose of1470 cGy on the surface of the stent, the ³²P stent will require to havean activity of 0.93 μCi, and the ¹⁰³Pd stent will require an activity of160 μCi.

In conclusion, radiation can be used to induce cellular proliferation inthe intima, media, and adventitia of the artery. Both the single dose ofradiation and the fractionation of the total dose promote fibroblasticproliferation. The beta-emitting stents with the stated dose and doserate showed a pronounced neointimal response and little adventitialcellular proliferation. In contrast, the external beam irradiationshowed cellular proliferation from adventitia to intima. Thus, theseradioactive modalities can be used to promote cellular proliferation theselected region of the artery.

What is claimed is:
 1. An endovacular device for use to affect therepair of an intracranial aneurysm of a vessel comprising: anendovascular implant sized and dimensioned for placement into ananeurysmal sac of the intracranial aneurysm, the endovascular deviceincluding a radioactive isotope selected to irradiate at least a portionof the aneurysmal sac with radiation at a collective radiation dose andat a low dose rate for a period of time sufficient to cause an increasein the rate of at least one of cell proliferation, cellular adhesion andthrombus formation in the aneurysmal sac to affect accelerated repair ofthe intracranial aneurysm.
 2. The endovascular device according to claim1, wherein the radiation dose is in the range of about 1 Gy to about 600Gy, and the low dose rate of is in the range of about 1 cGy/hr to about320 cGy/hr.
 3. The endovascular device according to claim 2 wherein, theradiation dose is in the range of about 1 Gy to about 25 Gy, and theselected low dose rate of is in the range of about 1 cGy/hr to about 15cGy/hr.
 4. The endovascular device according to claim 1 wherein, theendovascular device is provided by a coil emboli.
 5. The endovasculardevice according to claim 4 wherein, the coil emboli is composed a metalselected from the group including stainless steel and platinum.
 6. Theendovascular device according to claim 1, wherein the endovasculardevice is provided by a radioactive seeds.
 7. The endovascular deviceaccording to claim 1, wherein the radioactive isotope is selected fromthe group consisting essentially of alpha, beta and gamma radioisotopes.8. The endovascular device according to claim 1, wherein saidradioactive isotope is selected from the group consisting essentially ofPhosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103(¹⁰³Pd) and Iodine 125 (¹²⁵I).
 9. A method for treatment of anintracranial aneurysm which is in the form of an aneurysmal sac, saidmethod comprising: providing an endovascular device that emits radiationat a selected radiation dose and at a selected low dose rate; andplacing the endovascular device into the aneurysmal sac to irradiate atleast a portion of the aneurysmal sac with radiation at the collectiveradiation dose and at the low dose rate for the sufficient period oftime sufficient to cause an increase in the rate of at least one of cellproliferation, cellular adhesion and thrombus formation in theaneurysmal sac to affect accelerated repair of the intracranialaneurysm.
 10. The method according to claim 9, further including:selecting the radiation dose in the range of about 1 Gy to about 600 Gy,and selecting the low dose rate of in the range of about 1 cGy/hr toabout 320 cGy/hr.
 11. The method according to claim 10, furtherincluding: selecting the radiation dose in the range of about 1 Gy toabout 25 Gy, and selecting the low dose rate of in the range of about 1cGy/hr to about 15 cGy/hr.
 12. The method according to claim 9, furtherincluding: selecting a coil emboli as the endovascular device.
 13. Themethod according to claim 12, further including: selecting thecomposition of the coil emboli as a metal selected from the groupincluding stainless steel and platinum.
 14. The method according toclaim 9, further including: selecting radioactive seeds as theendovascular device.
 15. The method according to claim 9, furtherincluding: anchoring said endovascular device into the aneurysmal sac.16. The method according to claim 12, wherein said selecting a coilemboli includes selecting coil emboli emitting a radioisotope from thegroup consisting essentially of alpha, beta and gamma radioisotopes. 17.The method according to claim 14, wherein said selecting radioactiveseeds includes selecting radioactive seeds emitting a radioisotope fromthe group consisting essentially of alpha, beta and gamma radioisotopes.18. The method according to claim 9, wherein said providing anendovascular device includes selecting an endovascular device emitting aradioisotope from the group consisting essentially of alpha, beta andgamma radioisotopes.
 19. The method according to claim 12, wherein saidselecting a coil emboli includes selecting coil emboli emitting aradioisotope from the group consisting essentially of Phosphorus 32(³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103 (¹⁰³Pd) andIodine 125 (¹²⁵I).
 20. The method according to claim 9, wherein saidproviding an endovascular device includes selecting an endovasculardevice emitting a radioisotope from the group consisting essentially ofPhosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103(¹⁰³Pd) and Iodine 125 (¹²⁵I).
 21. The method according to claim 9,further including: irradiating the at least a portion of the aneurismalsac with said radiation from the endovascular device for the sufficientperiod of time of about 3 months.
 22. A method for treatment of anintracranial aneurysm which is in the form of an aneurysmal sac, saidmethod comprising: providing an endovascular device having a radioactiveisotope selected to emit radiation at a low dose rate; and placing andanchoring the endovascular device into the aneurysmal sac for a periodof time sufficient to expose at least a portion of the aneurysmal sac tothe radiation at a selected radiation dose and at the selected low doserate to cause an increase in the rate of at least one of cellproliferation, cellular adhesion and thrombus formation in theaneurysmal sac to affect accelerated repair of the intracranialaneurysm.
 23. The method according to claim 22, further including:selecting the radiation dose in the range of about 1 Gy to about 600 Gy,and selecting the low dose rate of in the range of about 1 cGy/hr toabout 320 cGy/hr.
 24. The method according to claim 23, furtherincluding: selecting the radiation dose in the range of about 1 Gy toabout 25 Gy, and selecting the low dose rate of in the range of about 1cGy/hr to about 15 cGy/hr.
 25. The method according to claim 22, furtherincluding: selecting a coil emboli as the endovascular device.
 26. Themethod according to claim 22, farther including: selecting radioactiveseeds as the endovascular device.
 27. The method according to claim 22,wherein said providing and anchoring an endovascular device includesselecting an endovascular device emitting a radioisotope from the groupconsisting essentially of alpha, beta and gamma radioisotopes.
 28. Themethod according to claim 22, wherein said providing and anchoring anendovascular device includes selecting an endovascular device emitting aradioisotope from the group consisting essentially of Phosphorus 32(³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103 (¹⁰³Pd) andIodine 125 (¹²⁵I).
 29. The method according to claim 22 furtherincluding: selecting an activity of the endovascular device based uponthe density of the material composing the endovascular device.
 30. Amethod of fabricating an endovascular device for the treatment of anintracranial aneurysm which is in the form of an aneurysmal sac, saidmethod comprising: providing an endovascular device for the placementand anchoring into the aneurysmal sac; and causing the endovasculardevice to become radioactive to emit radiation at a selected radiationdose and at a selected low dose rate such that exposure of at least aportion of the aneurysmal sac to the radiation for a sufficient periodof time causes an increase in the rate of at least one of cellproliferation, cellular adhesion and thrombus formation in theaneurysmal sac to affect accelerated repair of the intracranialaneurysm.
 31. The method according to claim 30, further including:selecting the radiation dose in the range of about 1 Gy to about 600 Gy,and selecting the low dose rate of in the range of about 1 cGy/hr toabout 320 cGy/hr.
 32. The method according to claim 31, furtherincluding: selecting the radiation dose in the range of about 1 Gy toabout 25 Gy, and selecting the low dose rate of in the range of about 1cGy/hr to about 15 cGy/hr.
 33. The method according to claim 30, furtherincluding: selecting a coil emboli as the endovascular device.
 34. Themethod according to claim 33, further including: selecting thecomposition of the coil emboli as a metal selected from the groupincluding stainless steel and platinum.
 35. The method according toclaim 30, further including: selecting radioactive seeds as theendovascular device.
 36. The method according to claim 30, wherein saidcausing the endovascular device to become radioactive is performed byattaching a radioisotope to the endovascular device.
 37. The methodaccording to claim 30, wherein said causing the endovascular device tobecome radioactive is performed by implanting a radioisotope into theendovascular device.
 38. The method according to claim 36, furtherincluding: selecting the radioisotope from the group consistingessentially of alpha, beta and gamma radioisotopes.
 39. The methodaccording to claim 37, further including: selecting the radioisotopefrom the group consisting essentially of alpha, beta and gammaradioisotopes.
 40. The method according to claim 36, further including:selecting the radioisotope from the group consisting essentially ofPhosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca), Palladium 103(¹⁰³PD) and Iodine 125 (¹²⁵I).
 41. The method according to claim 37,further including: selecting the radioisotope from the group consistingessentially of Phosphorus 32 (³²P), Yttrium 90 (⁹⁰Y), Calcium 45 (⁴⁵Ca),Palladium 103 (¹⁰³Pd) and Iodine 125 (¹²⁵J).